NZ304641A

NZ304641A - Tricyclic carbamate derivatives for inhibition of g-protein function and treating proliferative diseases

Info

Publication number: NZ304641A
Application number: NZ304641A
Authority: NZ
Inventors: W Robert Bishop; Ronald J Doll; Alan K Mallams; F George Njoroge; Joanne M Petrin; John J Piwinski; Ronald L Wolin; Arthur G Taveras; Stacy W Remiszewski
Original assignee: Schering Corp
Priority date: 1995-03-24
Filing date: 1996-03-21
Publication date: 1999-04-29
Also published as: EP0817632A1; ES2187642T3; US5977128A; DE69626104T2; KR19980703250A; CA2216231C; DE69626104D1; AU5189196A; AU714308B2; US5721236A; AR001413A1; WO1996030018A1; US5728703A; JP3001983B2; EP0817632B1; CA2216231A1; MX9707192A; TW323278B; JPH10505103A; US6300338B1

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 304641 9 New Zealand No. International No. 304641 PCT/US96/03312 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 24.03.1995; Complete Specification Filed: 21.03.1996 Classification:(6) C07D401/14; A61K31/495 Publication date: 29 April 1999 Journal No.: 1439 Title of invention: Tricyclic carbamate compounds useful for inhibition of g-protein function and for treatment of proliferative diseases Name, address and nationality of applicant(s) as in international application form: SCHERING CORPORATION, a New Jersey corporation of 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States of America NEW ZEALAND PATENTS ACT 1953 complete specification SB WO 96/30018 PCT/US96/03312 TRICYCLIC CARBAMATE COMPOUNDS USEFUL FOR INHIBITION OF G-PftOTEIN FUNCTION AND FOB TREATMENT 5 OF PROLIFERATIVE DISEASES International Publication Number W092/11034, published July 1992, discloses a method of increasing the sensitivity of a tumor to an 10 antineoplastic agent, which tumor is resistant to the antineoplastic agent, by the concurrent administration of the antineoplastic agent and a potentiating agent of the formula: wherein Y is hydrogen, substituted carboxylate or substituted sulfonyl. For 15 example, Y* can be, amongst others, •COOR> wherein R* is C1 to C6 alkyl or substituted alkyl, phenyl, substituted phenyl, C7 to C12 aralkyl or substituted aralkyl or -2, -3, or -4 piperidyl or N-substituted piperidyl. Y* can also be, amongst others, SO2R wherein R* is C1 to C6 alkyl, phenyl, substituted phenyl, C7 to C12 aralkyl or substituted aralkyl. Examples of 20 such potentiating agents include 11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines such as Loratadine. To acquire transforming potential, the precursor of the Ras oncoprotein must undergo famesyiation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes 25 this modification, farnesyi protein transferase, have therefore been suggested as anticancer agents for tumors in which Ras contributes to transformation. Mutated, oncogenic forms of ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et a!., Science, Vol. 260, 1834 to 1837, 30 1993). A welcome contribution to the art would be compounds useful for the inhibition of farnesyi protein transferase. Such a contribution is provided by this invention. -2- S1JMMARY OF THg INVENTION 30 4 64 1 Inhibition of farnesyi protein transferase by tricyclic compounds of this invention has not been reported previously. Thus, described but not claimed a method for inhibiting farnesyi protein transferase using tricyclic compounds of this invention which: (i) potently inhibit farnesyi protein transferase, but not geranylgeranyl protein transferase I. in vitro: (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyi acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyi acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras. Also described but not claimed is a method for inhibiting the abnormal growth of ceils, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs. The novel compounds of this invention are: 1 7 MAR 1999 RECEIVED 10 15 20 - 3 - T on 0*^0 — e> 4 (803.00) .CH3 and X&>1. Td r AO In a further aspect, the present invention provides a pharmaceutical composition, for use in inhibiting the growth of abnormal cells, comprising a pharmaceutical^ acceptable carrier and an effective amount of the compound of the invention. In a still further aspect, the present invention provides the use of a compound of the invention for the manufacture of a medicament for use in inhibiting the growth of abnormal cells. Also described but not claimed are the compounds CQOr° ^ I (800.00) O A aX) - iNiTlUCiUnL r,;,AnIV Oi-rlC.: or u.z. 1 7 MAR 1999 received 3a / ^ c These compounds are used in the methods described. Preferred compounds useful her-ein are represented by Formulas 801.00, 802.00, 803.00, 804.00 and 805.00. Also described but not claimed is a method for inhibiting tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular, there is described a method for inhibiting the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, bladder carcinoma, and myelodysplastic syndrome (MDS). proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes i.e., the Ras gene itself is not activated by mutation to an oncogenic form- Also described but not claimed is a method for inhibiting —r-rrrivY Crr Or I\I.Z. (followed by page 4) 1 7 MAR 1999 % 4- <u1 with said inhibition being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is 5 activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, Ick, lyn, fyn), may be inhibited by the tricyclic compounds described herein. The compounds of this invention inhibit farnesyi protein transferase and the famesyiation of the oncogene protein Ras. Further described but not 10 claimed is a method of inhibiting ras farnesyi protein transferase, in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyi protein transferase, is useful in the treatment of the cancers described above. 15 The tricyclic compounds useful in the methods of this invention inhibit abnormal cellular growth. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus matting them useful in the treatment of proliferative diseases such as 20 tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyi protein transferase, and thus show antiproliferative activity against ras transformed cells. DETAILED DESCRIPTION OF THE INVENTION 25 Certain compounds of the invention may exist in different isomeric (e.g., enantiomors and diastereoisomers) forms. The invention contemplates ail such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included. The compounds of the invention can exist in unsolvated as well as 30 solvated forms, including hydrated forms, e.g., hemi-hydrate. in general, the solvated forms, with pharmaceutical^ acceptable solvents such as water, EtOH and the like are equivalent to the unsolvated forms for purposes of the invention. Certain basic tricyclic compounds also form pharmaceutical^ 35 acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, iNTELLZCi tv.L •i.KiY Orrivw OF N.Z. 1 7 MAR 1999 » 30a6a1 -5- phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt 5 in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar 10 solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention. All such acid and base salts are intended to be pharmaceutical^ acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding 15 compounds for purposes of the invention. Compounds 801.00, 803.00 and 805.00 may be made by the methods described in WO 95/10515, published April 20, 1995 (e.g. see the preparations described for Formula 400.00), and by the methods described in the examples below. 20 in the examples, MH+ represents the molecular ion plus hydrogen of the molecule in the mass spectrum. Also, the following solvents and reagents are referred to herein by the abbreviations indicated: methanol (MeOH); ethyl acetate (EtOAc); and N,N-dimethylformamide (DMF). 25 PREPARATIVE EXAMPLF 1 '~"CQ3" o 'N H Step A; •■■•i sir, i r un of n.z, o n m »o moq WO 96/30018 -6- PCT/US96/03312 10 Cool 50.0 g (20.5 mmol) of 8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one to 0°C and slowly add 75 mL of sulfur monochloride over 20 minutes. Add 25 mL (48.59 mmol) of Br2 over 15 minutes, then heat at 95°C for 20 hours. Add 12.5 mL (24.3 mmol) of Br2 over 15 minutes and heat for 24 hours more. Cool vhe mixture and slowly add it to a mixture of CH2CI2 and 1N NaOH (aqueous) at 0°C. Wash the organic phase with water dry over MgSC>4. and concentrate in vacuo to a residue. Chromatograph (silica gel, 500 mL o? CH2CI2, then 0.2%-5% (10% concentrated NH4OH in MeOH)-CH2Cl2), then rechromafograph (silica gel, 3-8.5% EtOAc/hexane) to give 8.66 g of the product compound. Mass Spec.: MH+ - 322 Step B: "X&Or" —~x&y CI OH 15 Combine 6.84 g (21.2 mmol) of the product of Step A 160.5 mL of MeOH and treat with 1.1709 g of NaBH4 as described in Preparative Example 7, Step A, of WO 95/10515, to give 5.93 g of the product compound. MH+326 20 Step C: 25 "X&Cra -CI OH Combine 5.93 g (18.3 mmol) of the product of Step B and 116 mL of anhydrous toluene, cool to 0°C, and slowly add (dropwise) a solution of 2.465 g (33.9 mmol) of SOCI2 in 23 mL of anhydrous toluene over a poriod of 0.5 hours. Stir at 0°C for 1.5 hours and at 0°-25°C for 2 hours, then work up as described in Preparative Example 7, Step 8, of WO 95/10515, to give the product compound. ^ WO 96/30018 -7- PCT/US96/03312 SIselQ: ~<£Cr —ZX&Cra 0 N H React 18.3 mmol of the product of Step C with 9.94 g (91.5 mmol) of piperazine via the procedure described in Preparative Example 7, Step C, 5 of WO 95/1 Cr * 5, to give 8.0 g of the title compound. Mass Spec.: MH+ = 394 PREPARATIVE EXAMPLE 2 -CI o 'N k/ 10 Combine 10 g (31.9 mmol) of the product of Preparative Example 7, Step C, of WO 95/10515,100 mL of dry CH2CI2 and slowly (dropwise) add the solution to a mixture of 5.17 g (31.9 mmol) of carbonyldiimidazole in 150 mL of dry CH2CI2 over 0.75 hours. Stir at 0°C for 2 hours, wash with water, dry over MgSO* and concentrate in vacuo to a residue. 15 Chromatograph (silica gel, 2% (10% conc. NH4OH in MeOH)/CH2Cl2) to give 8.71 g of the title compound. Mass Spec.: MH+ = 40B.2 Using the product of Preparative Example 1, Step D, and essentially the same procedure as described for Preparative Example 2, the following compound is prepared: ^ WO 96/30018 -8- PCT/US96/03312 10 If" . »■ CI Preparative Example 2-A N Mass Spec.: MH+ = 488.2 o k/ PREPARATIVE EXAMPLE 3 .coci H3C—N >—O Combine 10 mL of dry CH2CI2 and 914.6 mL (28.1 mmol) of a 1.93 M solution of phosgene in toluene, cool to 0°C and slowly add (dropwise) a solution of 0.6484 g (5.62 mmol) of 3-hydroxy-1-N-methylpiperidine, 1.214 mL (15 mmol) of pyridine and 10 mL of dry CH2CI2, over 10 min., then stir at 0°-25°C for 2 hours. Purge excess phosgene with N2 then concentrate in vacuo to give the title compound. EXAMPLE 1 -ci 'N ? N. ijo or "o Combine 12 mL of dry CH2CI2 and 12.58 mL (23.9 mmol) of a 28% soution of phosgene in toluene, cool to 0°C under Ar atmosphere and 15 slowly add (dropwise) a solution of 0.5 g (1.59 mmol) of the product of Preparative Example 7, Step C, of WO 95/10515, 0.515 mL (6.36 mmol) of pyridine and 12 mL of dry CH2CI2, over 0.75 hours, then warm the mixture to 12°C over 0.5 hours. Purge excess phosgene with Ar then concentrate in vacuo to a residue. Add 10 mL of DMF, 0.515 mL of pyridine and 0.885 20 g (7.95 mmol) of 3-hydroxypyridine-1-N-oxide and stir at 25°C for 18 hours. Dilute with CH2CI2, wash with sat. NaHCOa (aqueous) and dry WO 96/30018 -9- PCT/US96/03312 over MgSQ4- Concentrate in vacuo to a residue and chromatograph (silica gal, 1.5% (10% NH4OH in MeOH)/CH2CI2) to give 0.186 g of the title compound. Mass Spec.: 451.3 Br ci EXAMPLE 2 XQCr r 1 ? X-O Combine 0.1 g (0.205 rsmol) of the product of Preparative Example 2-A, 0.0463 g (0.205 mmol) of 2nBr2,0.0913 g (0.822 mmol) of 3-hydroxypyridine-1-N-oxide and 3 mL of dry DMF, and heat the mixture at 10 90°C for 51 hours, stir at 25°C for 19 hours. Concentrate in vacuo to a residue and cfcs uograph (silica gel, 2% (10% NH4OH in MeOH)/CH2Cl2) to give 0.0812 g of the title compound. Mass Spec.: MH+ = 531.1 Using the starting compounds indicated and following essentially 15 the same procedure as described for Example 2, the following compounds are obtained: Starting Compound Product Compound Analytical Data 3-hydroxy-1-N-methylpiperidine and Preparative Example 2 C&Cra Ox <AcAJ Example 2-A Mass Spec.: MH+ = 455.25 96/30018 • 10- PCT/US96/03312 3-hydroxy-1-N-methylpiperidine and Preparative Example 2-A "X&Cr r i fHa n Mass Spec.: MH+ = 533.15 Example 2-B EXAMPLE 3 cP>° ^ ^ch3 Combine 0.5 g (1.6 mmol) of the product of Preparative Example 7, Step C, of WO 95/10515, 0.849 g (4.8 mmol) of the title compound of Preparative Example 3, and 10 mL of 1:1 pyridine/CH2Cl2, and stir at 25°C for 19 hours. Workup as described for Example 4, of WO 95/10515, and chromatograph (silica gel, 3% (10% NH4OH in MeOH)/CH2Cl2) to give 0.5231 g of the title compound. Mass Spec.: MH+ = 455.25 Using the starting compound indicated and following essentially the same procedure as described for Example 3, the following compound is obtained: Starting Compound Product Compound Analytical Data Preparative Example 1 rNy ^ J /v ^CH3 N j^ N 3 Example 3-A Mass Spec.: MH+ = 533.15 ^WO 96/30018 - 11 - PCT/US96/03312 FPT IC50 (inhibition of Farnesyi Protein Transferase by in vitro enzyme assays) and COS IC50 (Cell-Based Assay) were determined using the methods described in WO 95/10515. The results are given in Table 1 below. Cell Mat Assays and in vivo anti-tumor studies could be done by the methods described in WO 95/10515. 10 15 20 25 IABLE-1 FPT INHIBITION COMPOUND FPT IC50 (uM) COS IC50 (UM) (800.00) Example 1 0.01-10 (801.00) Example 2 0.01-10 (802.00) Example 3 10-100 — (803.00) Example 3-A 0.01-10 10-100 (804.00) Example 2-A 0.01-10 (805.00) Example 2-B 0.01-10 — 30 The data demonstrate that the compounds of the invention are inhibitors of Ras-CVLS famesyiation by partially purified rat and human brain farnesyi protein transferase (FPT). The data also show that there are compounds of the invention which can be considered as potent (IC50 <10 fiM) inhibitors of Ras-CVLS famesyiation by partially purified rat brain farnesyi protein transferase (FPT)~see Table 1. For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutical^ acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 70 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify. WO 96/30018 PCT/US96/03312 - 12- Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid form preparations may also include solutions for intranasal 5 administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutical^ acceptable carrier, such as an inert compressed gas. Also included are solid form preparations which are intended to be 10 converted, shortly before use, to liquid form preparations for either oral or parenteral administration. .Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, 15 lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. Preferably the compound is administered orally. Preferably, the pharmaceutical preparation is in unit dosage form. 20 In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, more preferably from 25 about 1 mg. to 300 mg, according to the particular application. TTie actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which 30 are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. The amount and frequency of administration of the compounds of 35 the invention and the pharmaceutical^ acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended dosage regimen is • WO 96/30018 -13- PCT/US96/03312 oral administration of from 10 mg to 2000 mg/day preferably 10 to 1000 mg/Jay, in two to four divided doses to block tumor growth. The compounds are non-toxic when administered within this dosage range. The following are examples of pharmaceutical dosage forms which contain a compound of the invention. The scope of the invention in its pharmaceutical composition aspect is not to be limited by the examples provided. Pharmaceutical Dosaoe Form Examples EXAMPLE A No. Ingredients mg/iablet mg/tablet 1. Active compound 100 500 2. Lactose USP 122 113 3. Corn Starch, Food Grade, as a 10% paste in Purified Water 30 40 4. Corn Starch, Food Grade 45 40 5. Magnesium Stearate 3 _Z Total 300 700 10 Method of Manufacture Mix item Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with item No. 3. Mill the damp granules through a coarse screen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. 15 Screen the dried granules if necessary and mix with Item No. 4 and mix for • 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to appropriate size and weigh on a suitable tablet machine. EXAMPLE B - Capsules 20 No. Ingredient mg/capsule mg/capsule 1. Active compound 100 500 2. Lactose USP 106 123 3. Com Starch, Food Grade 40 70 4. Magnesium Stearate NF 7 Z Total 253 700 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 96/30018 - 14- PCT/US96/03312 Method of Manufacture Mix Item Nos. 1,2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Rll the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine. 5 While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall 10 within the spirit and scope of the present invention. 15 304641 WHAT WE CLAIM IS: l • A compound selected from a compound of the formula: 2 • A pharmaceutical composition, for use in inhibiting the growth of abnormal cells, comprising a pharmaceutically acceptable carrier and an effective amount of a compound of Claim 1 • 3 ■ The use of a compound of Claim l for the manufacture of a medicament for use in inhibiting the growth of abnormal cells. and IWTELLtCiUML i ^OiTnTYOrriCZ OF HZ. 17 MAR 1999 30 464 1 4 • A compound as claimed in Claim i selected from the compound of the formulae defined therein substantially as herein described with reference to any example thereof. 5 ■ A pharmaceutical composition as claimed in Claim 2 for use in inhibiting the growth of abnormal cells substantially as herein described with reference to any example thereof. 6. The use of a compound as claimed in Claim 3 substantially as herein described with reference to any example thereof. r-oeFogAtlosJ. By the authorised agents end of claims iNTELLiECT"" 1 7 MAR 1999 RECEivrn </div>